2. Academic Validation
  3. MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1

  • Cardiovasc Diabetol. 2024 May 9;23(1):164. doi: 10.1186/s12933-024-02254-7.
Yuqiong Chen # 1,  Su Li # 2,  Bo Guan # 3,  Xiaopei Yan 4,  Chao Huang 5,  Yingqiang Du 6,  Fan Yang 7 8,  Nannan Zhang 6,  Yafei Li 6,  Jian Lu 9,  Jiankang Wang 6,  Jun Zhang 6,  Zhangwei Chen 10,  Chao Chen 11,  Xiangqing Kong 12 13
Affiliations

Affiliations

  • 1 Department of Cardiology, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 215000, Suzhou, Jiangsu Province, China. cosmoscyq@163.com.
  • 2 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China.
  • 3 Department of Geriatrics, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China.
  • 4 Department of Respiratory Medicine, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, Suzhou, China.
  • 5 Ministry of Science and Technology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, 215002, Suzhou, Jiangsu, China.
  • 6 Department of Cardiology, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 215000, Suzhou, Jiangsu Province, China.
  • 7 Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Affiliated Hospital of Medical School, Nanjing Drum Tower Hospital, Nanjing University, 210008, Nanjing, China.
  • 8 Branch of National Clinical Research Center for Metabolic Diseases, 210008, Nanjing, China.
  • 9 Department of Critical Care Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
  • 10 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, China. chen.zhangwei@zs-hospital.sh.cn.
  • 11 Department of Cardiology, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 215000, Suzhou, Jiangsu Province, China. chenchao0321@njmu.edu.cn.
  • 12 Department of Cardiology, Gusu School, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Nanjing Medical University, 215000, Suzhou, Jiangsu Province, China. Kongxq@njmu.edu.cn.
  • 13 Department of Cardiology, Gulou District, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing City, Jiangsu Province, China. Kongxq@njmu.edu.cn.
  • # Contributed equally.
PMID: 38724987 DOI: 10.1186/s12933-024-02254-7
Abstract

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to Cardiovascular Disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting Glutathione Peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial Ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial Ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and Ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

Keywords

Cardiac microvascular injury; Diabetic cardiomyopathy; Drp1; MAP4K4; S-nitrosylation.

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